The synthesis of a number of deaza derivatives of methotrexate, aminopterin, and 5,10-methylenetetrahydrofolate will be undertaken. Target compounds include 5-deazaaminopterin, 5-deazamethotrexate, 5, 10-dideazaaminopterin, 5-deaza-5, 10-methylenetetrahydrofolic acid, 4-amino-4-deoxy-5-deaza-5,10-methylenefolic acid, 4-amino-4-deoxy-5, 10-methylenetetrahydrofolic acid, 5-deaza-5, 10-methylenefolic acid, 4-amino-4-deoxy-10-deaza-5, 10-deaza-5, 10-methylenetetrahydrofolic acid and 10-deaza-5, 10-methylenetetrahydrofolic acid. These compounds, which are designed to be potent inhibitors of dihydrofolate reductase and/or thymidylate synthetase, will be evaluated as antineoplastic drugs through enzyme inhibition studies, in vitro metabolic and cytotoxicity studies in cultured cell lines, and in vivo screening against experimental animal tumors.